Search

Individuals can exhibit differences in metabolism caused by the interplay of genetic background, nutritional input, microbiota, and other environmental factors(1–4). It is difficult to connect differences in metabolism to genomic variation and derive underlying molecular mechanisms in humans due to differences in diet and lifestyle, among others. Here, we introduce the nematode Caenorhabditis elegans as a model to study inter-individual variation in metabolism. By comparing three wild strains and the commonly used N2 laboratory strain, we find differences in the abundances of both known and previously undescribed metabolites. Novel metabolites include conjugates between 3-hydroxypropionate (3HP) and several amino acids (3HP-AAs) that are much higher in abundance in one of the wild strains. 3HP is an intermediate in the propionate shunt pathway, which is activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed(5). We demonstrate that increased 3HP-AA accumulation is caused by genetic variation in HPHD-1, for which 3HP is a substrate. Our results suggest that 3HP-AA production represents a ‘shunt-within-a-shunt’ pathway to accommodate a reduction-of-function allele in hphd-1. This study provides a first step to developing metabolic network models that capture individual-specific differences of metabolism and more closely represent the diversity found in entire species.

OBJECTIVE The adverse health effects of short sleep duration (i.e., six or fewer hours per night) are well established, including an increased risk of cardiovascular disease (CVD) and related mortality. However, there is heterogeneity in perceived sleep need among habitual short sleepers (HSS), with a sizable minority reporting no sleep-related daytime dysfunction. It has not been determined whether health risk associated with short sleep duration is consistent across individuals with and without reported dysfunction. The current study examined self-rated health (SRH), previously demonstrated to predict CVD risk, and objective CVD risk among HSS with and without reported dysfunction in the National Health and Nutrition Examination Surveys (NHANES). METHOD Participants were adults age 40-79 in the 2005-2006 and 2007-2008 NHANES cycles. Assessments included the single item SRH (poor to excellent), self-reported average sleep duration, and self-reported daytime sleep-related dysfunction. Ten-year atherosclerotic CVD and high lifetime CVD risk (≥39%) were calculated using previously validated algorithms. RESULTS HSS with no reported dysfunction rated their overall health significantly better than those with reported dysfunction; however, the "no dysfunction" HSS group evidenced modestly, though significantly, higher 10-year CVD risk compared with their dysfunction-reporting counterparts. High lifetime CVD risk, including younger adults age 20-39, was slightly higher for persons not reporting dysfunction, with the exception of short sleepers at the highest level of dysfunction who had the highest prevalence of high lifetime risk. CONCLUSIONS Findings suggest that the absence of perceived sleep-related dysfunction does not confer lower CVD risk, despite higher SRH. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The recently discovered modular glucosides (MOGLs) form a large metabolite library derived from combinatorial assembly of moieties from amino acid, neurotransmitter, and lipid metabolism in the model organism C. elegans. Combining CRISPR-Cas9 genome editing, comparative metabolomics, and synthesis, we show that the carboxylesterase homologue Cel-CEST-1.2 is responsible for specific 2-O-acylation of diverse glucose scaffolds with a wide variety of building blocks, resulting in more than 150 different MOGLs. We further show that this biosynthetic role is conserved for the closest homologue of Cel-CEST-1.2 in the related nematode species C. briggsae, Cbr-CEST-2. Expression of Cel-cest-1.2 and MOGL biosynthesis are strongly induced by starvation conditions in C. elegans, one of the premier model systems for mechanisms connecting nutrition and physiology. Cel-cest-1.2-deletion results in early death of adult animals under starvation conditions, providing first insights into the biological functions of MOGLs.

Recent studies of animal metabolism have revealed large numbers of novel metabolites that are involved in all aspects of organismal biology, but it is unclear to what extent metabolomes differ between sexes. Here, using untargeted comparative metabolomics for the analysis of wildtype animals and a series of germline mutants, we show that C. elegans hermaphrodites and males exhibit pervasive metabolomic differences. Several hundred small molecules are produced exclusively or in much larger amounts in one sex, including a host of previously unreported metabolites that incorporate building blocks from nucleoside, carbohydrate, lipid, and amino acid metabolism. A subset of male-enriched metabolites is specifically associated with the presence of a male germline, whereas enrichment of other compounds requires a male soma. Further, we show that one of the male germline-dependent metabolites, an unusual dipeptide incorporating N,N-dimethyltryptophan, accelerates the last stage of larval development in hermaphrodites. Our results serve as a foundation for mechanistic studies of how the genetic sex of soma and germline shape the C. elegans metabolome and provides a blueprint for the discovery of sex-dependent metabolites in other animals.

We describe two complementary approaches based on a convergent [4+2] logic toward the synthesis of amorfrutins, cannabinoids, and related plant metabolites. An anionic cascade cyclization employing β-methoxycrotonates and β-chloro-α,β-unsaturated esters yielded amorfrutins in four linear steps and demonstrated utility of β-alkoxycrotonate-derived nucleophiles as functional equivalents of β-ketoester-derived dianions. Analogously, tandem Diels-Alder/retro-Diels-Alder cycloaddition of dimedone-derived bis(trimethylsiloxy)-dienes and α,β-alkynyl ester dienophiles provided facile access to resorcinol precursors of amorfrutins and cannabinoids, avoiding late-stage installation of prenyl or geranyl moieties as in previous approaches.

Stress associated with global health threats such as the coronavirus disease 2019 (COVID-19) pandemic and related containment efforts may be associated with significant sleep disruption. Stress-related sleep disturbance is an established transdiagnostic risk factor; thus, identifying associations with coping strategies may inform future intervention efforts. The current study examined secondary control-oriented coping strategies, including positive reappraisal, which may be particularly effective in the context of stressors characterized by high uncertainty and low controllability such as a pandemic.The current study (totalParticipants reported high levels of stress due to the pandemic onset, including difficulties with time management, difficulties with work or school, and worry about the future. Reappraisal and acceptance were both associated with higher concurrent PA, lower NA, and less increase in sleep disturbance; however, positive reappraisal was the only coping strategy that predicted unique variance in increased sleep disturbance.Current findings add to our understanding of stress adaptation in response to stressors characterized by high severity, high uncertainty, and low controllability, such as the COVID-19 pandemic, and suggest that positive reappraisal and PA may foster resilience to stress-related sleep disturbance. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The recently discovered modular glucosides (MOGLs) form a large metabolite library derived from combinatorial assembly of moieties from amino acid, neurotransmitter, and lipid metabolism in the model organism C. elegans. Combining CRISPR-Cas9 genome editing, comparative metabolomics, and synthesis, we show that the carboxylesterase homologue Cel-CEST-1.2 is responsible for specific 2-O-acylation of diverse glucose scaffolds with a wide variety of building blocks, resulting in more than 150 different MOGLs. We further show that this biosynthetic role is conserved for the closest homologue of Cel-CEST-1.2 in the related nematode species C. briggsae, Cbr-CEST-2. Expression of Cel-cest-1.2 and MOGL biosynthesis are strongly induced by starvation conditions in C. elegans, one of the premier model systems for mechanisms connecting nutrition and physiology. Cel-cest-1.2-deletion results in early death of adult animals under starvation conditions, providing first insights into the biological functions of MOGLs.

Reactive electrophilic intermediates such as coenzyme A esters play central roles in metabolism but are difficult to detect with conventional strategies. Here, we introduce hydroxylamine-based stable isotope labeling to convert reactive electrophilic intermediates into stable derivatives that are easily detectable via LC–MS. In the model system Caenorhabditis elegans, parallel treatment with (14)NH(2)OH and (15)NH(2)OH revealed >1000 labeled metabolites, e.g., derived from peptide, fatty acid, and ascaroside pheromone biosyntheses. Results from NH(2)OH treatment of a pheromone biosynthesis mutant, acox-1.1, suggested upregulation of thioesterase activity, which was confirmed by gene expression analysis. The upregulated thioesterase contributes to the biosynthesis of a specific subset of ascarosides, determining the balance of dispersal and attractive signals. These results demonstrate the utility of NH(2)OH labeling for investigating complex biosynthetic networks. Initial results with Aspergillus and human cell lines indicate applicability toward uncovering reactive metabolomes in diverse living systems.

Signaling molecules derived from attachment of diverse metabolic building blocks to ascarosides play a central role in the life history of C. elegans and other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that a pathway mediating formation of intestinal lysosome-related organelles (LROs) is required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Similar to modular ascarosides, the modular glucosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism, suggesting that modular glucosides, like the ascarosides, may serve signaling functions. We further show that carboxylesterases that localize to intestinal organelles are required for the assembly of both modular ascarosides and glucosides via ester and amide linkages. Further exploration of LRO function and carboxylesterase homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms.

Few nucleoside-derived natural products have been identified from animals, despite the ubiquity of nucleosides in living organisms. Here, we use a combination of synthesis and the emerging electron microscopy technique microcrystal electron diffraction to determine the structures of several N3-(β-glucopyranosyl)uric acid derivatives in Caenorhabditis elegans. These noncanonical gluconucleosides further integrate an ascaroside moiety, for which we present a shortened synthetic route. The production of a phosphorylated gluconucleoside is influenced by evolutionarily conserved insulin signaling.

Few nucleoside-derived natural products have been identified from animals, despite the ubiquity of nucleosides in living organisms. Here, we use a combination of synthesis and the emerging electron microscopy technique microcrystal electron diffraction to determine the structures of several N(3)-(β-glucopyranosyl)uric acid derivatives in Caenorhabditis elegans. These noncanonical gluconucleosides further integrate an ascaroside moiety, for which we present a shortened synthetic route. The production of a phosphorylated gluconucleoside is influenced by evolutionarily conserved insulin signaling.

Study ObjectivesReport the first prevalence estimates of advanced sleep phase (ASP), familial advanced sleep phase (FASP), and advanced sleep–wake phase disorder (ASWPD). This can guide clinicians on the utility of screening for extreme chronotypes both for clinical decision-making and to flag prospective participants in the study of the genetics and biology of FASP.MethodsData on morning or evening sleep schedule preference (chronotype) were collected from 2422 new patients presenting to a North American sleep center over 9.8 years. FASP was determined using a severity criterion that has previously identified dominant circadian mutations in humans. All patients were personally seen and evaluated by one of the authors (C.R.J.).ResultsOur results demonstrate an ASP prevalence of 0.33%, an FASP prevalence of 0.21%, and an ASWPD prevalence of at least 0.04%. Most cases of young-onset ASP were familial.ConclusionsAmong patients presenting to a sleep clinic, conservatively 1 out of every 300 patients will have ASP, 1 out of every 475 will have FASP, and 1 out of every 2500 will have ASWPD. This supports obtaining a routine circadian history and, for those with extreme chronotypes, obtaining a family history of circadian preference. This can optimize treatment for evening sleepiness and early morning awakening and lead to additional circadian gene discovery. We hope these findings will lead to improved treatment options for a wide range of sleep and medical disorders in the future.

Study Objectives Much of what we assume about the effects of short sleep duration on neural reward processing derives from total sleep deprivation studies. Although total sleep deprivation appears rare, habitual short sleep is common: 30% of working US adults report habitually sleeping ≤ 6 hours/night. It remains largely unknown whether habitual short sleepers exhibit similar reward processing brain activation patterns to those observed following total sleep deprivation in prior studies. Therefore, our aim was to test objectively reward processing brain activation patterns associated with self-reported habitual short sleep duration in a large sample. Methods Nine hundred and fifty-two adult participants from the Human Connectome Project database were grouped on reported habitual short (≤6 hours) vs. medium-length (7–9 hours) sleep duration using the Pittsburgh Sleep Quality Index (PSQI). Reward processing brain activation was examined using a gambling task during functional magnetic resonance imaging (fMRI). Subject-level covariates for age, sex, continuous sleep duration, daytime dysfunction, and PSQI total score are provided as supplemental analyses. Results Brain activation patterns revealed expected reward processing-related activation for age and sex. However, activation for sleep duration, dysfunction, and PSQI score did not correspond to those evident in previous total sleep deprivation studies. Conclusions Self-reported short sleep duration, perceived sleep-related dysfunction, and sleep quality via PSQI do not appear to be meaningfully associated with activation in well-described regions of the human neurobiological reward circuit. As these findings are counter to prior results using experimental sleep deprivation, future work focused on more direct comparisons between self-reported sleep variables and experimental sleep deprivation appears warranted.

In this study, our objectives were to 1) Examine performance on an objective measure of reward-related cognitive impulsivity (delay discounting) among self-reported habitual short sleepers not reporting daytime dysfunction in comparison to those reporting dysfunction and conventional sleepers; 2) Inform the debate regarding what type and duration of short sleep meaningfully influences cognitive impulsivity; 3) Compare the predictive utility of sleep duration and perceived daytime dysfunction to other factors previously shown to influence cognitive impulsivity via delay discounting performance (age, income, education, and fluid intelligence). We analyzed data from 1,190 adults from the Human Connectome Project database. Participants were grouped on whether they reported habitual short (≤ 6 hours) vs. conventional (7 to 9 hours) sleep duration and whether they perceived daytime dysfunction using the Pittsburgh Sleep Quality Index. Results indicated that short sleepers not reporting dysfunction evidenced increased delay discounting compared to conventional sleepers, but were not significantly different from short sleepers reporting dysfunction. Regardless of perceived dysfunction, all short sleepers exhibited increased delay discounting compared to all conventional sleepers. Of the variables examined, self-reported sleep duration was the strongest predictor of delay discounting behavior between groups and across all 1,190 participants. We conclude that individuals who report habitual short sleep are likely to exhibit increased reward-related cognitive impulsivity regardless of whether they perceive sleep-related daytime impairment. Therefore, there is reason to suspect that these individuals exhibit more daytime dysfunction, in the form of reward-related cognitive impulsivity, than they may assume. Current findings suggest that assessment of sleep duration over the prior month has meaningful predictive utility for human reward-related impulsivity.

Background Approximately 30% of the U.S. population reports recurrent short sleep; however, perceived sleep need varies widely among individuals. Some “habitual short sleepers” routinely sleep 4–6 hr/night without self-reported adverse consequences. Identifying neural mechanisms underlying individual differences in perceived sleep-related dysfunction has important implications for understanding associations between sleep duration and health. Method This study utilized data from 839 subjects of the Human Connectome Project to examine resting functional connectivity associations with self-reported short sleep duration, as well as differences between short sleepers with versus without reported dysfunction. Functional connectivity was analyzed using a parcellation covering the cortical, subcortical, and cerebellar gray matter at 5 mm resolution. Results Self-reported sleep duration predicts one of the primary patterns of intersubject variance in resting functional connectivity. Compared to conventional sleepers, both short sleeper subtypes exhibited resting fMRI (R-fMRI) signatures consistent with diminished wakefulness, potentially indicating inaccurate perception of functionality among those denying dysfunction. Short sleepers denying dysfunction exhibited increased connectivity between sensory cortices and bilateral amygdala and hippocampus, suggesting that efficient sleep-related memory consolidation may partly explain individual differences in perceived daytime dysfunction. Conclusions Overall, current findings indicate that R-fMRI investigations should include assessment of average sleep duration during the prior month. Furthermore, short sleeper subtype findings provide a candidate neural mechanism underlying differences in perceived daytime impairment associated with short sleep duration.

Previous research suggests that the dorsal dentate gyrus (DG) hippocampal subregion mediates spatial processing functions. However, a novel role for the DG in temporal processing for spatial information has begun to emerge based on the development of a computational model of neurogenesis. According to this model, adult born granule cells in the DG contribute to a temporal associative integration process for events presented closer in time. Currently, there is a paucity of behavioral evidence to support the temporal integration theory. Therefore, we developed a novel behavioral paradigm to investigate the role of the dDG in temporal integration for proximal and distal spatial events. Male Long-Evans rats were randomly assigned to a control group or to receive bilateral intracranial infusions of colchicine into the dDG. Following recovery from surgery, each rat was tested on a cued-recall of sequence paradigm. In this task, animals were allowed to explore identical objects placed in designated spatial locations on a cheeseboard maze across 2 days (e.g., Day 1: A and B; Day 2: C and D). One week later, animals were given a brief cue (A or C) followed by a preference test between spatial location B and D. Control animals had a significant preference for the spatial location previously paired with the cue (the temporal associate) whereas dDG lesioned animals failed to show a preference. These findings suggest that selective colchicine-induced dDG lesions are capable of disrupting the formation of temporal associations between spatial events presented close in time.